The present invention relates to a method for providing sustained release of molecules. More particularly, the invention relates to the release of molecules, e.g., insolubilized proteins, from a reservoir of discrete, implantable gelled masses, with or without surrounding semipermeable membranes.
Incorporation of different core materials within gelled masses, either with or without surrounding semipermeable membranes, has been investigated for a number of years. Much early work involved the use of gelled masses or microcapsules for a variety of testing and storage purposes. However, gelled masses have a tendency to break down over time in physiological solutions. Because of this, some form of membrane is often used to make the gelled masses into a semipermeable capsule. U.S. Pat. No. 4,352,883, issued Oct. 5, 1982, upon application of Dr. Franklin Lim, discloses a basic procedure for encapsulating core materials, including viable cells, within capsules having semipermeable membranes.
Capsules made with the Lim technique may be engineered to have membranes which are permeable to molecules below a particular molecular weight but are substantially impermeable to high molecular weight molecules and to cells. The pores of the membranes are believed to comprise tortuous paths defined by the interstices of the membrane structure. Passage of molecules above a particular molecular weight is hindered by these tortuous path pores, and above a certain higher molecular weight and corresponding larger effective molecular dimensions, the hindrance is sufficiently great that the membrane is substantially impermeable to these molecules.
Porosity control is an important factor in a number of important uses of such microcapsules. For example, the microcapsule membrane can be used for differential screening; that is, to separate molecules on a molecular weight basis. U.S. Pat. No. 4,409,331, issued Oct. 11, 1983, also on an application of Dr. Franklin Lim, discloses a method of differential screening wherein lower molecular weight substances secreted by cells within the capsule may traverse the membrane while other, higher molecular weight materials are confined within the capsules. Such capsules can simplify greatly collection of a substance of interest.
A preferred embodiment of this encapsulation technique involves the formation of shape-retaining gelled masses which contain the core material (the material to be encapsulated) followed by deposition of a membrane on the surface of the gelled masses. The membrane is formed as relatively high molecular weight materials contact the gelled masses and form ionic cross-links with the gel. Lower molecular weight cross-linking polymers permeate further into the structure of the gelled masses, resulting in a reduction of pore size. The duration of membrane formation can also affect pore size since for a given pair of reactants, the longer the gelled masses are exposed to the cross-linking polymer solution, the thicker and less permeable the membrane.
While the techniques for porosity control and membrane formation disclosed in the Lim patent can form acceptable membranes, many applications of capsule technology are better achieved by use of membranes having improved porosity control and better uniformity. The Lim porosity control techniques do not allow fine tuning of the membrane porosity, but rather set rough differential filtering limits.
U.S. Pat. No. 4,663,286, issued May 5, 1987, on application of Dr. Wen-Ghih Tsang et al., discloses modifications and improvements for porosity control on the basic Lim techniques. Gelled masses are formed when a water-soluble polyanionic polymer is gelled by cross-linking with multivalent cations. The gelled masses are expanded, and a more uniform gel ball created, by soaking the gelled masses in an aqueous solution of monovalent cations to remove some of the polyvalent cations. The semipermeable membrane is formed about the expanded gel ball using the basic Lim technique. The improvement in uniformity of the gel balls caused by the soaking step before membrane formation allows more uniform pore size and leads to better porosity control.
In order to obtain release of core material from the capsule without disrupting the capsule membrane, the conventional technique has been to reliquify the unreacted gel by soaking the capsules in a chelating agent that removes the multivalent cations and destroys the cross-linking, thereby dissolving the gel. However, once the capsule interior is reliquified, the only porosity control mechanism is the pore size of the membrane. To obtain sustained release from the interior of the capsule after reliquification, two factors are necessary: the molecule to be released must be smaller then the molecular weight cut-off of the membrane, and there must be a strong osmotic gradient across the membrane driving the released material at a substantially constant rate. U.S. Pat. No. 4,690,682, issued Sept. 1, 1987, on application of Dr. Franklin Lim, discloses such a technique. However, in order to sustain the osmotic gradient, a very large reservoir of the core material must be maintained within the capsule and the core material which has been released must be taken away from the exterior of the capsule at a relatively rapid rate. These limitations may not be feasible.
Accordingly, an object of the invention to provide a mechanism for sustained release of insolubilized molecules into a solution in which they are soluble.
Another object of the invention is to provide a method of controlling the gel state of a gelled ball, either with or without encapsulating within a semipermeable membrane, to facilitate sustained release of molecules encapsulated within the gelled masses.
A further object of the invention is to provide a method of releasing medication in a time-controlled manner.
These and other objects and features will be apparent following description and the drawing.